Jaw-Tumor Hyperparathyroidism Syndrome as Reproductive Disease Model

一位来自HPT-JT家族的26岁无妊娠妇女因终身月经过多导致贫血而被转诊。她的家族成员已知携带CDC73/HRPT2的L95P错义突变，并且一些人患有HPT-JT。病人希望对她的月经过多和怀孕的能力进行管理。对患者进行基因分型，发现为杂合的种系L95P副纤白蛋白错义突变。

A 26 year old nulligravida woman from a family with HPT-JT was referred for life-long menorrhagia resulting in anemia. Members of her family were known to carry a L95P missense mutation in CDC73/HRPT2, and several were affected with HPT-JT. The patient desired management of her menorrhagia and the ability to conceive. The patient was genotyped and found to be heterozygous for a germline L95P parafibromin missense mutation. Physical examination was notable for a large everted external cervical os. Transvaginal ultrasound and magnetic resonance imaging demonstrated an enlarged endometrial lining with thickening of the junctional zone. Operative hysteroscopy revealed a uterine cavity filled with atypical, fibrous endometrial polyp-like structures which extended from the fundus and down through the cervix. The polyps were surgically removed with electrocautery and multiple mucous filled cysts were seen. Histologic examination of these polypoid structures revealed benign uterine adenomyomas. A new progesterone IUD was placed in the uterine cavity in the operating room for management of menorrhagia. Five months later the patient presented with persistence of menorrhagia. Staining for aromatase was then performed on her histologic tissue samples from the prior surgery. This staining revealed an over-expression of aromatase within her adenomyomas as compared to normal controls without adenomyomas. The patient was started on an aromatase inhibitor. Upon follow up six months after the aromatase inhibitor was started, the patient noted decreased uterine bleeding and her endometrial lining was thin at 4mm. Post-operatively, the patient received medical therapy with an aromatase inhibitor and a progesterone intrauterine device. This treatment was continued for a total of ten months resulting in continued improvement in her symptoms. The patient desired pregnancy and a follow-up hysteroscopy documented dramatic improvement in the uterine cavity with a few smaller polyps the largest of which was 3mm. The IUD and the remaining small polyps were surgically removed. The aromatase inhibitor was discontinued three months after surgery and the patient became spontaneously pregnant with her next ovulatory cycle. She had an uncomplicated pregnancy resulting in a term spontaneous vaginal delivery of a 4479gm female. Imaging demonstrated an enlarged endometrial lining and thickening of the junctional zone. At operative hysteroscopy, multiple atypical endometrial polyp-like lesions filled the entire uterine cavity and were removed. Histologic evaluation demonstrated the lesions to be adenomyomas with an abundance of aromatase expression. Postoperative treatment included an aromatase inhibitor. The patients menorrhagia, which had previously been resistant to progesterone IUD therapy, resolved with the aromatase inhibitor. After ten months of this treatment, the aromatase inhibitor was discontinued and a repeat hysteroscopy revealed a markedly improved uterine cavity. The patient subsequently became pregnant on her first natural cycle and delivered a healthy term infant. To our knowledge, assessment of aromatase expression in the uterine pathology of HPT-JT has not been reported. As part of this project, the use of aromatase inhibitors resulted in marked clinical improvement, decreased menorrhagia, and the ability to conceive. This may represent a novel therapy for the medical therapy of benign uterine lesions in women with HPT-JT. In addition to developing novel clinical therapies for this disorder, we have utilized this rare condition to study gynecologic conditions in the laboratory. Currently, efforts are underway to create novel in vitro cell lines to study this disorder. These cell lines could become important systems used to study benign endometrial diseases, as well as atypical uterine malignancies, where cells lines for in vitro study are lacking.